Abuse resistant drugs, using method and preparation method
The application is application number is 200880103447.4, and the applying date is on August 12nd, 2008, and denomination of invention is the divisional application of the Chinese patent application of " abuse resistant drugs, using method and preparation method ".
This application claims the priority of U.S.Provisional Serial 60/955,584 submitted on August 13rd, 2007, its by reference its entirety be incorporated at this.
Background technology
The present invention relates generally to field of medicinal compositions, and reduce inappropriate drug administration and they indicate or the compositions of probability that the mode of OTC (over-the-counter) uses with non-in particular to being designed for.The present invention can comprise any medicine, the medicine particularly abused.Specifically, it relates to analgesic drug product, alleviates or eliminate the medicine (psychotherapeutic drug) of anxiety attack, beta stimulant and sleeping pill.These universal medicines have the probability of abuse that can cause overdose, addiction, suboptimum effect and/or death.
Especially, the present invention relates to and have, but be not limited to the anti-abuse compositions (such as analgesic drug product, anxiety outbreak medicine, sleeping pill or beta stimulant) on diffusion layer and barrier layer; The purposes of this compositions in the dosage form of disease therapy or illness; And preparation has the method for the compositions of the prevention abuse on diffusion layer and barrier layer.In some embodiments, compositions also comprises extension layer.
OPIOIDS agonist is that described opioid receptor is present in brain, spinal cord and gastrointestinal tract by being incorporated into the specific proteins being called opioid receptor and the material worked.When being incorporated into some opioid receptor in brain and spinal cord when these medicines, they can block the transmission of pain information to brain effectively.Opioid analgesic, such as oxycodone, morphine, oxymorphone, hydrocodone and hydromorphone are successful and the upper useful analgesic drug product for the treatment of.Unfortunately, change emotion due to them and/or cause the ability of excited sensation (" excited "), they also provide the serious threat of abuse arbitrarily.The sustained release forms of this medicine available at present attracts misuser especially, because sustained release effect is by crushing or rolling said preparation and destroy, described sustained release forms contains relatively a large amount of medicines, is intended to discharge from said preparation within a period of time extended.The material (preparation namely crushed) produced no longer controls the release of medicine.According to medicine, misuser then can this material of (1) snuffing, and (2) swallow this material or (3) by this substance dissolves in water or wine, intravenous injection subsequently it.Therefore, the dosage of the medicine contained in preparation is absorbed immediately by nasal mucosa or GI mucosa (respectively for snuffing or swallow), or injects and be applied to systemic circulation (for IV injection).
These abuse methods produce in single tablet or capsule the quick bio availability of the medicine of the relative high dose contained, and make misuser's " excited ".Peak serum concentration (Cmax) height correlation of excited sensation or " excited " and medicine.Although this high plasma concentration can by once taking several rapid releases or continuous release tablet and obtaining, but misuser is prevented from doing like this, because it is more difficult to obtain multiple tablet, and may more importantly, (the high blood plasma level of usual medicine is the function of a period of time extended along with the risk of the serious over administration increased once to take the adjoint very high dosage of several tablets; Produce high area under curve: the integration of Plasma concentrations versus time, be also known as abbreviation " AUC ").In order to reduce the risk of over administration, typical misuser preferably will obtain high peak serum concentration from single tablet or capsule.In the scientific terminology of pharmacologist, typical misuser shows as and makes Cmax maximize and AUC is minimized, or makes Cmax/AUC alternatively than maximizing.
In some instances, misuser drinks and takes rapid release and/or delayed release preparation to reach more rapidly " excited ".Sometimes, preparation is placed in water or wine by misuser, thus extracts medicine with accelerated mode.These liquid known use the time of sometimes reducing and reaching peak serum concentration and Cmax after medicament administration altogether.Sometimes, preparation is placed in other solvents by misuser, such as freon, dichloromethane, ethanol and acetone, thus extracts medicine, then can be injected.Another technology that misuser extracts medicine used from dosage form (such as tablet) wipes the coating of tablet, tablet is pressed into trickle powder, powder is placed in sterilized water, then pour liquid into syringe.In addition, by crushing, rolling and chew and generally physically destroy this dosage form.
Because relatively simple method (crush, roll, chew and/or be dissolved in water or wine) can be used for single delayed-release tablet or capsule preparations to change into and can abuse form, therefore in fact the dosage form of these routines does not provide obstruction to potential misuser.
Due to the report of lasting abuse and transfer, FDA strengthens recently
(
) (controlled release oxycodone hydrochloride) tablet label in warning and preventive measure part, this tablet be approval be used for the treatment of the narcotics of moderate to severe pain.
containing oxycodone hydrochloride (usable intensity 10,20,40,80 and 160mg), a kind of OPIOIDS agonist with the addiction probability similar to morphine.
with controlled release form supply, and be intended to for moderate to severe pain provides the alleviation reaching 12 hours.FDA warning set forth especially, and this tablet must be taken by full wafer, and by means of only oral.When this tablet is chewed or crushed, and its content is swallowed, snuffing enters nostril or dissolve and intravenous injection subsequently time, controlled release mechanism is destroyed, and the oxycodone of danger dose become can biological utilisation, it may the user of this product lethal, particularly user first.
In recent years, existing many reports that oxycodone is shifted and abused in several state.Such as, the medicine transfer control office of DEA reports 700 examples in the U.S. between June in January, 2000 to calendar year 2001
usurp.Some in the case of these reports create serious consequence, comprise death.
Oxycodone is the control medicine in the list II of controlled substance method (CSA), and this method is implemented by drug enforcement administration (DEA).Although in fact list II provides the maximum that may control of CSA to the medicine of approval, in fact law enforcement agency is difficult to the transfer of legal prescription or the control of misuse.Although abuse, misuse and transfer are the potential problems of all OPIOIDS comprising oxycodone, when suitably using under the careful supervision doctor, OPIOIDS is the very important part of the medical substances of control pain.The current available preparation of this medicine is designed to Orally administered, but does not comprise preventing or hindering and such as chew, inject and the mechanism of unsuitable application process of snuffing.This represents, opens a large amount of legal prescriptions create serious problem in the U.S.; Such as in the U.S., the medical application from 1996 to OPIOIDS in 2000 adds 400%.
The problem of abuse is obvious and long-term, and the effort designing new anti-abuse or anti-abuse preparation is unsuccessful to a great extent.U.S. Patent number 3,980,766 describe and mix Absorbable rod solid, and when its aqueous solution concentrates, it causes increase sharply (gelation) of viscosity.U.S. Patent number 4,070,494 describe to be enough to provide the amount of drug resistance to mix nontoxic water to water extract can the material of gelation, therefore postpones the release of medicine.U.S. Patent number 6,309,668 describe and are used for Orally administered tablet, and it contains two or more layers, and it is included in one or more medicines in each layer of the separation of tablet and one or more gellant.Embodiment in this patent all describes when combining with the water yield needed for dissolved substance, and the tablet of conventional immediate release preparation and generation forms gel; Therefore this one dosage type low temperature reduces medicine from the extraction ratio tablet.Although it should be noted that these compositionss can prevent the abuse by injection, this method can not prevent by crushing and swallow or the abuse of snuffing said preparation, these be with
the abuse methods of relevant usual report.
U.S. Patent number 6,277,384,6,375,957 and 6,475,494 describe the peroral dosage form comprising Orally active OPIOIDS agonist and Orally active OPIOIDS antagonist and combine with certain proportion, when oral delivery, this ratio makes it need in the curee looked after to be effectively analgesia but disgusting.Although this preparation successfully can prevent abuse, it also has the probability had side effects in rational patient.
U.S. Patent Application Publication No. 2007/0066537 discloses anti-abuse OPIOIDS, and wherein this OPIOIDS is incorporated into nicotinic acid, biotin or peptide.
U.S. Patent Application Publication No. 2006/0104909 discloses the pharmaceutical composition comprising OPIOIDS and anti-interference substrate, described anti-interference substrate comprises the cross linked polymer of one or more adhesions, and it can be combined with OPIOIDS so that OPIOIDS can not discharge immediately substantially from polymer.Preferred aspect uses water-insoluble host material further, comprise the insensitive material of pH, such as ethyl cellulose, cellulose acetate, vinyl acetate/vinyl chloride copolymer, acrylate/methacrylate copolymer, polyethylene glycol oxide, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose, hydroxypropyl cellulose, triglyceride, hydrogenated vegetable oil, triglyceride gather the protein of alkoxy alkyl, fat, wax and water-insoluble Partial digestion.Surface coatings material comprises hydrophobic polymer, such as pharmaceutically acceptable acrylate copolymer, such as acrylic acid and methacrylic acid copolymer, methylmethacrylate copolymer, ethoxyethyl methacrylates, methacrylic acid cyanaoethyl methacrylate, Eudragit E100, poly-(acrylic acid), polymethylacrylic acid, methacrylic acid alkylamide copolymer, poly-(methyl methacrylate), poly-(methacrylic anhydride), methyl methacrylate, polymethacrylates, polyvinyl lactam and glycidyl methacrylate copolymer.In certain preferred aspects, acrylate copolymer is made up of one or more ammonium methacrylate ester copolymers.Ammonium methacrylate ester copolymer is well known in the art, and in NFXVII, be described as the acrylic acid of the quaternary ammonium group with low content and the copolymer be polymerized completely of methacrylic acid.
U.S. Patent Application Publication No. 2005/0281748 discloses and OPIOIDS is incorporated into lipid or fatty acid to produce abuse resistant drugs.
The object of this invention is to provide a kind of pharmaceutical composition, it significantly reduces the unsuitable probability used or use of medicine, but when using as shown, can the effective dosage of delivery treatments.Especially, the present invention caters to the demand to a kind of medicine, and described medicine and conventional formulation contrast, and reduces with unsuitable intensity, degree, frequency and the speed of using the appearance occurring " excitement " effect.
Summary of the invention
The present invention relates to a kind of anti-abuse combination of oral medication, it comprises: the barrier layer comprising the first polymer; With the diffusion layer comprising the second polymer covering barrier layer substantially, wherein diffusion layer is incorporated into barrier layer, and comprises and to be evenly distributed in very much in the second polymer and from the medicine of diffusion layer diffusion in gastrointestinal (GI) road.Described pharmaceutical composition optionally comprises extension layer, and it comprises easily extensible polymer, and wherein extension layer is covered substantially by barrier layer.
The invention still further relates to a kind of combination of oral medication, it comprises the medicine of pharmaceutical effective amount, wherein pharmaceutical composition is formulated, so that when pharmaceutical composition is applied to curee with physically destroyed form, in a period of time, medicine is equal to or less than drug release rate when pharmaceutical composition is used with complete form substantially from the speed that compositions discharges, and described a period of time is selected from by 2 hours, 4 hours, 8 hours and the group that forms for 16 hours.
The invention still further relates to a kind of combination of oral medication, it comprises the medicine of pharmaceutical effective amount, wherein pharmaceutical composition is formulated, so that when pharmaceutical composition is applied to curee with physically destroyed form, the amount that in a period of time, medicine discharges from compositions, substantially identical or lower compared to the amount of the drug release when pharmaceutical composition is used with complete form, preferably lower than 20%, more preferably less than 30%, and most preferably lower than 40%, described a period of time is selected from by 2 hours, 4 hours, 8 hours and the group that forms for 16 hours.In the context of this application, phrase " substantially identical " refers in (+/-) 30%, preferably in (+/-) 20%, and more preferably in (+/-) 10%.
The invention still further relates to a kind of combination of oral medication, it comprises the medicine of pharmaceutical effective amount, wherein pharmaceutical composition is formulated, so that when pharmaceutical composition thereof wine or when taking together with wine, the speed that in a period of time, medicine discharges from compositions, substantially identical or lower compared to the speed of the drug release when pharmaceutical composition is not used together with wine, preferably lower than 40%, more preferably less than 30%, and most preferably lower than 20%, described a period of time is selected from by 2 hours, 4 hours, 8 hours and the group that forms for 16 hours.
The invention still further relates to a kind of combination of oral medication, it comprises the medicine of pharmaceutical effective amount, wherein pharmaceutical composition is formulated, so that when pharmaceutical composition is used with complete form, after 8 hours, the medicine of the amount of at least 50% is released, and when pharmaceutical composition is used with physically destroyed form, after 1 hour, be no more than 40%, the medicine preferably more than the amount of 30% is released.
The invention still further relates to a kind of combination of oral medication, it comprises the medicine of pharmaceutical effective amount, wherein pharmaceutical composition is formulated, so that when pharmaceutical composition is used with complete form, after 1 hour, the medicine of the amount of at least 90% is released, and when pharmaceutical composition is used with physically destroyed form, after 1 hour, the medicine being no more than the amount of 75% is released.
The invention still further relates to a kind of method preparing anti-abuse combination of oral medication, it comprises: form barrier layer, wherein barrier layer comprises the first polymer; And diffusion layer is applied to basic covering barrier layer on barrier layer, wherein diffusion layer comprises the second polymer and is evenly distributed on the medicine in the second polymer; And diffusion layer is incorporated into barrier layer preferably by physical bond.
The invention still further relates to a kind of method preparing anti-abuse combination of oral medication, it comprises: form extension layer, it comprises easily extensible polymer; And by barrier application on extension layer substantially to cover extension layer, wherein barrier layer comprises the first polymer; And diffusion layer is applied to basic covering barrier layer on barrier layer, wherein diffusion layer comprises the second polymer and is evenly distributed on the medicine in the second polymer; And diffusion layer is incorporated into barrier layer preferably by physical bond.In some embodiments, barrier layer is applied on extension layer by spraying or dry coating.
The invention still further relates to a kind of method for the treatment of illness, it comprises uses pharmaceutical composition of the present invention to its patient of needs.
The invention still further relates to a kind of combination of oral medication, it comprises the medicine of pharmaceutical effective amount, wherein pharmaceutical composition is formulated, so that when pharmaceutical composition is applied to curee with physically destroyed form, the intensity of the excitement that excited intensity realizes after being substantially equal to or less than the physically destroyed bioequivalent compositions of the method used not containing anti-abuse.
Accompanying drawing explanation
Fig. 1 contrasts suitably percentage ratio rate of release and the figure of time that (complete) takes the tablet prepared according to embodiment 31 and the same piece agent formulation taking ground form.For anti-abuse oxycodone tablet (preferred embodiment), at deionized water; 100RPM; Basket method; Comparison in-vitro release rate in 900mL, intact tablet is compared to the tablet ground.
Fig. 2 is contrast
the tablet ground and the percentage ratio rate of release of the tablet ground of preparation of embodiment 31 and the figure of time.For anti-abuse oxycodone tablet (preferred embodiment), at deionized water; 100RPM; Basket method; Comparison in-vitro release rate in 900mL, OxyContin RTM is compared to anti-abuse oxycodone tablet.
Fig. 3 be the display feature of the present invention utilizing Microsoft Excel Software program to obtain body in simulation drawing.As grind tablet and snuffing subsequently mill pulverized powder after as shown in, rapid release commercially available at present or the tablet of delayed release will show Cmax-1.Identical tablet, when complete picked-up, will be shown as Cmax-2, because the speed absorbed postpones because of the physiologic factor in gastrointestinal tract.Bioequivalence tablet formulation of the present invention is by feature identical with Cmax-2 curve for display.But tablet of the present invention, when grinding also snuffing, will be shown as lower Cmax-3.
Fig. 4 be contrast suitably (complete) take according to embodiment 31 prepare tablet and take " incision form " same piece agent formulation percentage ratio rate of release and the figure of time.For anti-abuse oxycodone tablet (preferred embodiment), at deionized water; 100RPM; Basket method; Comparison in-vitro release rate in 900mL.
Detailed description of the invention
Abuse resistant drugs compositions of the present invention concept behind provides the medicine of necessary amount to realize pharmacy effect (such as pain relief) to patient, and reduce potential misuser and transform compositions thus stand " excited ", or the ability of induction quick death.Usually abused, and be therefore suitable for medicine of the present invention particularly including analgesic drug product (such as OPIOIDS), anxiety outbreak medicine, sleeping pill and beta stimulant.
Anti-abuse compositions of the present invention is being destroyed when the physical integrity of dosage form containing said composition, and the preparation produced subsequently by snuffing, inject or swallow time, can postpone or at least not significantly increasing medicament from the release of dosage form.Compositions, when it exists with the form outside complete form, is " being physically destroyed ".This is by accomplished in many ways, and such as by chewing, mince, grind, crush or being placed in solvent, described solvent such as contains those solvents and/or the water of alcohol (such as ethanol).Therefore, compositions of the present invention provides obstruction to the unsuitable common methods used, because medicine can not from preparation immediately and promptly discharge, and because with complete formulations Comparative, the actual amount of drug release may be lowered, wherein saidly unsuitablely use the intravenous injection comprising the medicine being dissolved in solvent, and the nose of the preparation crushed is used or Orally administered.When by indicated using, medicine, in gastrointestinal (GI) road, discharges from compositions more step by step preferably by dissolving and/or flooding mechanism.
According to an embodiment, abuse resistant drugs compositions of the present invention comprises: the barrier layer comprising the first polymer; With the diffusion layer comprising the second polymer covering barrier layer substantially, wherein diffusion layer is incorporated into barrier layer, and comprises and to be evenly distributed in very much in the second polymer and in the gastrointestinal tract from the medicine of diffusion layer diffusion.Described pharmaceutical composition optionally comprises extension layer, and it comprises easily extensible polymer.Pharmaceutical composition comprises in the embodiment of extension layer wherein, and barrier layer covers extension layer substantially.
Anti-abuse compositions of the present invention can comprise be designed for Orally administered arbitrary delayed release preparation and quick releasing formulation or both, described delayed release preparation has slow releasing in the typical body of medicine within the time of about 6 to about 24 hours or external, preferably the medicine of at least 80% was release in about 12 to about 24 hours, described quick releasing formulation has preferably at least 80%, more preferably at least 90%, and most preferably the medicine of at least 95% discharged in 1 hour.
Anti-abuse combination of oral medication can be any pharmaceutical dosage form, includes but not limited to tablet, capsule, microplate, granule, pill, lollipop, lozenge and coated capsule.In preferred embodiments, anti-abuse combination of oral medication is Tabules.
Anti-abuse combination of oral medication comprises in the embodiment of optional extension layer wherein, and extension layer is the innermost layer in three layers of pharmaceutical composition.Extension layer is preferably inert layer, and it is not containing any medicine, and it comprises easily extensible polymer.Extension layer preferably has about 0.5 to 15mm, more preferably from about 2 to 12mm, and the thickness of most preferably from about 4 to 10mm.The thickness of extension layer is preferably about 5% to 95% of tablet thickness, and more preferably from about 40% to 95%, and most preferably from about 50% to 90%.
In some embodiments, when the easily extensible polymer of optional extension layer is exposed to liquid, when preferably including the liquid of water and/or alcohol (such as ethanol), easily extensible Polymer absorption liquid, and preferably expand and/or form gel.Preferred hydrophilic polymer, the hydrophilic polymer most preferably expanded when contact liq and/or gel.In a preferred form, when extension layer in anti-abuse compositions by physical damage, and formed containing extension layer compositions fragment after, when being exposed to liquid, easily extensible polymer at least absorbs a part of liquid and forms gel.Gel preferably postpones the release of medicine from diffusion layer further.In addition, the viscosity of increase can make misuser be difficult to preparation to pour into syringe to be used for injection.Extension layer preferably includes the polymer existed with the weight range of 5% to 90% of the gross weight of dosage form.
The typical agent used in extension layer includes but not limited to methylcellulose, sodium carboxymethyl cellulose, methyl hydroxyethylcellulose, methylhydroxypropylcellulose, alginic acid, polyacrylic acid and tragacanth, or the combination of two or more in these materials.Most preferably hydroxypropyl emthylcellulose and polyacrylic acid, hydroxypropyl emthylcellulose is sometimes with trade (brand) name
sell, and polyacrylic acid is sometimes with trade (brand) name
sell.
Extension layer also can comprise disintegrating agent, such as cross-linking sodium carboxymethyl cellulose or Explotab, with auxiliary guarantee extension layer rapid dispersion in liquid.The added ingredient that can be present in extension layer includes but not limited to filler, dyestuff, lubricant or water permeation promoter, such as sodium chloride.High soluble polymer, disintegrating agent or its be combined in pharmaceutical field and widely known, and as skilled in the art to understand, any suitable high soluble polymer or disintegrating agent or equivalent material can with the present invention and embodiment conbined usage thereof.
Barrier layer is in the inside of diffusion layer.Some wherein pharmaceutical composition comprise in the embodiment of extension layer, extension layer is the innermost layer in three layers, and barrier layer covers extension layer substantially.The basic covering of extension layer refers to more than 80%, more preferably above 90% and the extension layer of override more than 95% is covered by barrier layer.The covering of 100% is most suitable.
Barrier layer preferably has about 0.1 to 2.5mm, more preferably from about 0.2 to 2.0mm, and the thickness of most preferably from about 0.5 to 1.5mm.The thickness on barrier layer is preferably about 5% to 50% of the gross thickness of compositions, and more preferably from about 8% to 30%, and most preferably from about 10% to 25%.
Barrier layer has many functions.Such as, barrier layer is used as the barrier between diffusion layer and extension layer, reduces when dosage form exists with complete form, can enter the amount of the liquid of extension layer.In addition, barrier layer is for improving the mechanical strength of compositions.
Barrier layer comprises polymer.Typical barrier polymers includes but not limited to that polyacrylate and copolymer thereof are (such as with trade (brand) name
nE30D sell those),
fS30D,
rS30D, from
's
from
's
and
nE30D and
mixture, Polyethylene Glycol, polyethylene glycol oxide, polyethylene, polypropylene, polrvinyl chloride, Merlon, polystyrene and similar polymer.The preferred polymers on barrier layer is polyacrylate and Polyethylene Glycol, and particularly polyacrylate dispersion.Pharmaceutical composition comprises in the embodiment of extension layer wherein, and barrier layer also can be bonded in extension layer containing binding agent with auxiliary its.The use of the polymer of antibiont degraded, binding agent or its combination is widely known in pharmaceutical field, and as skilled in the art to understand, any suitable antibiont polymer or adhesion promoter can with the present invention and embodiment conbined usage thereof.
Preferably, when the dosage form containing anti-Drug abuse compositions of the present invention is applied to curee with complete form, barrier polymers is not dissolved substantially in gastrointestinal tract, mucosa, blood vessel or lung.In addition, health is passed with largely insoluble form in barrier layer." substantially insoluble " refers to be less than 30%, is more preferably less than 20%, and the polymer being most preferably less than 10% is dissolved.
The basic covering barrier layer of diffusion layer.The basic covering on barrier layer refers to more than 80%, more preferably above 90%, and is covered by barrier layer most preferably more than the extension layer of 95%.The covering of 100% is most preferred.
Diffusion layer comprises polymer and medicine, is preferably substantially evenly distributed in the medicine in polymer." distributing substantially equably " refers to more than 80%, more preferably above 90%, and is equally distributed most preferably more than the medicine of 95%.The polymer of diffusion layer and pharmaceutical dispersions are employed and are incorporated into barrier layer.
Diffusion layer is preferably a thin layer, and it has the large surface area compared with the thickness of this layer.Diffusion layer preferably has about 0.1 to 1.0mm, more preferably from about 0.15 to 0.7mm, and the thickness of most preferably from about 0.2 to 0.4mm.The thickness of diffusion layer is preferably about 1% to 30% of tablet thickness, and more preferably from about 2% to 20%, and most preferably from about 3% to 10%.In a preferred embodiment of the invention, compared with the surface area of diffusion layer, diffusion layer is relative thin.
In some preferred embodiments, one or more containing dyestuff in each layer, when with liquid or saliva contacts, generations is dyeed or color by it.This can assist the anti-abuse feature of tablet of the present invention.The example of dyestuff includes but not limited to FD & CRed#3, FD & CRed#28 and FD & CBlue#1.
The medicine mixing pharmaceutical composition of the present invention can be any medicine, or any compositions of two or more medicines.But usually, one or more medicines will be often by the medicine abused, such as central nervous system stimulant and depressant.The example of central nervous system stimulant includes but not limited to amphetamine, and the agent of such as cocaine.The example of central nervous depressant includes but not limited to OPIOIDS class, barbiturates, Benzodiazepines and other antianxiety drugss and sleeping pill.The example of the compositions of two kinds of medicines comprises oxycodone and morphine.
The example of OPIOIDS includes but not limited to following: alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, Clonitazene, codeine, Desomorphine, dextromoramide, dezocine, diampromide, diamorphine, dihydrocodeine, paramorphan (dihydromorphine), dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, Pethidine, meptazinol, metazocine, methadone, metopon, morphine, Myrophine, papaverine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphine, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, pirinitramide, propheptazine, Promedol, properidine, dextropropoxyphene, sufentanil, tilidate and tramadol.Any OPIOIDS or its pharmaceutically acceptable salt or ester can be used for anti-abuse compositions.Preferred OPIOIDS comprises fentanyl, sufentanil, carfentanil, lofentanil, alfentanil, hydromorphone, oxycodone, morphine, hydroxycodone, dextropropoxyphene, pentazocine, methadone, tilidate, butorphanol, buprenorphine, levorphanol, codeine, oxymorphone, Pethidine and dihydrocodeinone.Preferred OPIOIDS comprises oxycodone, hydrocodone, codeine, morphine, oxymorphone and hydromorphone, and its pharmaceutically acceptable salt and ester.The most particularly preferred OPIOIDS is oxycodone and morphine, and pharmaceutically acceptable salt.
The example of barbiturates includes but not limited to enphenemal, and (it is sometimes with trade (brand) name
sell) and pentobarbital sodium (it is sometimes with trade (brand) name
sell).Usually the prescription of barbiturates is opened to treat anxiety, anxiety and sleep disorder.
The example of Benzodiazepines and Benzodiazepine derivant includes but not limited to that diazepam is (sometimes with trade (brand) name
sell), alprazolam is (sometimes with trade (brand) name
sell), triazolam (
) and estazolam (
).Usually Benzodiazepines prescription is outputed to treat anxiety, gross stress reaction and panic attack.
The example of another CNS inhibitor is Zaleplon, and it is sometimes with trade (brand) name
sell.
Although various types of CNS inhibitor works by different way, they can produce useful hypnosis or sedation in the individuality of illness suffering from such as sleep disorder and anxiety.But if these medicines of people's life-time service, its health can produce toleration, and larger dosage may be needed to realize initial effect.In addition, continuous print uses can cause physical dependence, and when minimizing or when stopping using, produces withdrawal symptom.Barbiturates and Benzodiazepines both have the probability of abuse, and should only use according to prescription.As OPIOIDS, the over administration of these medicines may be fatal.
Beta stimulant increases heart rate, blood pressure and metabolism, sometimes produces the happy and sensation of spirit and the alertness of raising.Usually open amphetamine-type such as methylphenidate (sometimes with trade (brand) name
sell) and dexamphetamine (sometimes with trade (brand) name
with
sell) prescription be used for the treatment of narcolepsy, attention-deficient/hyperactivity disorder, and do not respond the depression of other treatment.They are also used to the short term therapy of obesity.The individual energy addiction that can become sensation to the producible happiness of beta stimulant and enhancing.But the beta stimulant repeatedly taking high dose in the short time can produce hostility or paranoea.In addition, the beta stimulant taking high dose can produce jeopardously high fever and irregular heart beating.
The preferred embodiments of the invention comprise following medicine and amount: oxycodone or its pharmaceutically acceptable salt, and it exists with the amount of about 5mg to about 400mg; Morphine or its pharmaceutically acceptable salt, it exists with the amount of about 15mg to about 800mg; Hydromorphone or its pharmaceutically acceptable salt, it exists with the amount of about 1mg to about 64mg; Hydrocodone or its pharmaceutically acceptable salt, it exists with the amount of about 5mg to about 400mg; And oxymorphone or its pharmaceutically acceptable salt, it exists with the amount of about 4mg to about 80mg.
Except one or more medicines, diffusion layer contains one or more polymer.The example that can be used for the polymer of diffusion layer includes but not limited to, ethyl cellulose, quaternary ammonium acrylic or methacrylate polymer, acrylic or methacrylic acid ester copolymer or its mixture, it also can be used as sustained release agent.Common trade (brand) name comprises multiple grade
(all from
) and
(from
).The preferred polymers of diffusion layer is acrylic or methacrylic acid polymer, and particularly ethyl acrylate or methyl methacrylate dispersion.Polymer dispersion, the use of the polymer particularly worn and torn gradually is widely known in pharmaceutical field, and as skilled in the art to understand, any suitable polymer worn and torn gradually can with the present invention and embodiment conbined usage thereof.
Suitable wax can replace part or all of polymer in diffusion layer.Suitable wax comprises synthetic wax and native paraffin, and ceroidlike material, fat and lipid, hydro carbons (such as paraffin, Cera Flava, Brazil wax and similar substance), comprise the compositions of these materials.These materials dissolve slowly or completely insoluble in the gastrointestinal tract.The use of ceroidlike material is widely known in pharmaceutical field, and as skilled in the art to understand, any suitable ceroidlike material can with the present invention and embodiment conbined usage thereof.
Diffusion layer is also optionally containing continuing or delayed release and/or enteric coating.The example of this material is cellulose acetate phthalate, Hydroxypropyl Methylcellulose Phathalate, poly-phthalic acid acetic acid ethylene, methacrylic acid: acrylate copolymer, HPMCAS, lac, trimellitic acid cellulose acetate and composition thereof.Diffusion layer also can contain water-soluble polymer, such as polyvinylpyrrolidone, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, has from 1,700 to 20, the Polyethylene Glycol of the molecular weight of 000 and polyvinyl alcohol and monomer whose, and its mixture.The use continuing the material of coating, prolongation coating and enteric coating is widely known in pharmaceutical field, and as skilled in the art to understand, any suitable lasting coating, the material extending coating and enteric coating or similar agent can with the present invention and embodiment conbined usage thereof.
In preferred embodiments, for barrier layer and diffusion layer, acrylic acid coating be with aqueous dispersion use acrylic paint, its purchased from
pharma, trade mark is called
Medicine distributing substantially equably in the polymer of diffusion layer such as makes medicine discharge in the gastrointestinal tract with the desired rate determined, so that it discharges medicine lentamente.Diffusion layer can be immediate release layer or delayed release layer.Diffusion layer, preferably in reaching 24 hours, preferably maintains the release characteristic identical with conventional complete formutatibh, even when this layer is broken into smaller pieces.The existence of medicine in diffusion layer is considered to cause forming hole in the polymer of diffusion layer.The existence in hole makes diffusion layer wear and tear gradually, and drug release.The rate of release of medicine regulates by the size changing polymer orifices.The minimizing of the size of such as polymer orifices can reduce the rate of release of medicine.Diffusion layer is stretched or is exposed to solvent also will to reduce the size of polymer orifices, and reduce the rate of release of medicine.
Diffusion layer and barrier layer be combined with each other.Each layer is by any methods combining as known in the art.In some embodiments, each layer is chemically combined, or preferably, they are physically combined.In preferred embodiments, secondary or physical bond is formed between the layers by heat setting.In another preferred embodiment, each layer exists in powder form, and by using tablet machine physically to combine.In some embodiments, extension layer and group barrier layer can be prepared into bolus, and store a period of time, preferably reach seven days, as long as barrier layer is not eliminated.
Preferably, compositions formulated is consequently when pharmaceutical composition is physically damaged, and when the granule containing the pharmaceutical composition on diffusion layer and barrier layer is formed, the key in granule between diffusion layer and barrier layer is retained substantially.In a preferred embodiment of the present invention, destroy pharmaceutical product by this way and will cause diffusion synusia with stop synusia because destructive activity closely combines in granule.Therefore, in a preferred embodiment of the present invention, when producing granule with 500 order to 8 object scopes, the relative surface area of diffusion layer only will increase (be such as no more than 50%, preferably more than 25%, be most preferably not exceeding 10%) at edge.In a preferred embodiment of the present invention, the control of drug diffusion surface area, or even time destroyed, prevent medicine from discharging fast from medicine composition.
Being formed in of key between diffusion layer and barrier layer realizes in anti-abuse being important, because when dosage form of the present invention is by physical damage, the inner side of barrier layer protected diffusion layer, prevents the remarkable increase of drug release.Therefore, medicine maintains and substantially discharges gradually from the outside of diffusion layer with the speed of its design.
They by applying diffusion layer immediately after application barrier layer in conjunction with design feature, then together process and optimize by layer.
Diffusion layer polymer can drug loading wherein, and therefore after dosage form changes, prevents from medicine from inclining.Barrier layer and optional extension layer strengthen the anti-abuse feature of pharmaceutical composition.
Other component can join any one in each layer or all, condition is their not interference medicaments, and provides required benefit to medicine.Other the example of component this is: the plasticizer used in a known way, antiplastering aid, inert filler, lipophilic agent and pigment.The cohesiveness of the dispersible film substrate of water is by mixing coating simply to overcome by antiplastering aid.The example of antiplastering aid be metallic stearate, microcrystalline Cellulose, calcium phosphate,
200 and Talcum.Those skilled in the art will appreciate that the needs of other components this and apply the problem that it overcomes production, storage period or release characteristic.
The example of plasticizer used according to the invention comprises glyceryl triacetate, acetylated monoglyceride, olive oil, citroflex A-4, CitroflexA-2, glycerol, sorbitol, Polyethylene Glycol and polypropylene glycol.
Filler/diluent/binding agent can be mixed, the lactose of such as sucrose, sorbitol, mannitol, various grade, the microcrystalline Cellulose of various grade, dextrin, maltodextrin, starch or modified starch, sodium phosphate, calcium phosphate, calcium carbonate, gelatin, polyvinylpyrrolidone and sodium carboxymethyl cellulose.
Can disintegrating agent be used, such as cellulose derivative, comprise microcrystalline Cellulose, the hydroxypropyl cellulose of low replacement, cross-linked carboxymethyl cellulose sodium, alginic acid, insoluble polyvinylpyrrolidone and carboxymethyl starch sodium.
Fluidizer and lubricant can be mixed, such as stearic acid, metallic stearate, Talcum, wax and there is the glyceride of high melting temperature, silica sol, sodium stearyl fumarate, Polyethylene Glycol and alkyl sodium sulfate ester.
Surfactant can be used, such as non-ionic surface active agent (Polysorbate of various grade); Anion surfactant, such as docusate sodium and sodium lauryl sulphate, and cationic surfactant, such as benzalkonium chloride.The example of amphoteric surfactant is 1,2-diacyl-L-phosphatidylcholine.Preferred surfactant is
and Nanoxyl-100.
Other suitable pharmaceutically acceptable excipient can comprise and do coloring agent, flavoring agent, pH adjusting agent, stabilizing agent, wetting agent, resistant to dissolution agent and buffer agent.
Other layers one or more can be placed under extension layer, or between extension layer and barrier layer, or above diffusion layer or top.Such as, in some embodiments, extension layer does not directly contact barrier layer, because one or more layer can between extension layer and barrier layer.In other embodiments, extension layer can cover another layer be positioned under extension layer.In some embodiments, other the releasing layers one or more comprising one or more other drugs can be positioned at the top of diffusion layer.In some embodiments, other releasing layer can be delayed release layer or release layer.In some embodiments, delayed release layer and release layer all can be positioned at the top of diffusion layer.One or more other drugs can be any medicines, comprise the medicine of a part for the diffusion layer that may be compositions, such as central nervous stimulant and inhibitor, such as OPIOIDS, barbiturates, Benzodiazepines and amphetamine-type.Preferably, be release layer at the layer at the top of diffusion layer, and the medicine in release layer include but not limited to acetaminophen and NSAID (non-steroidal anti-inflammatory drug).
Due to feature described above, the abuse potential of pharmaceutical composition of the present invention is lowered.In addition, in some embodiments, described feature can prevent patient dosage form to be cut into the small pieces of a part of dosage containing intact tablet.Such as, attempt the patient of 80mg tablet being cut into 4 20mg tablet, by the 20mg tablet of cutting compared with unbroken 20mg tablet, required curative effect can not be realized.Be exactly this situation, because in this embodiment of the present invention, the 20mg tablet of incision can not be released in the medicine of the whole 20mg amounts in tablet.
Preferably, when suitably using with complete form, medicine discharges from diffusion layer with required rate of release, and the residue of pharmaceutical composition is with the health of inertia form by patient, because barrier layer prevents the residue of compositions to be destroyed in the gastrointestinal tract.Required rate of release can be usually available from the rate of release of desired use, is such as described in the prescription information relevant to business medicine.
Compositions comprises in the of the present invention preferred embodiment of extension layer wherein, the medicine of physical damage causes extension layer distributing containing between diffusion layer and the granule of thin barrier layer component, become the component of the granule containing diffusion layer and thin barrier layer component, or more two kinds of situations.Therefore, in a preferred embodiment of the present invention, once be exposed to body fluid or other liquid, granule containing diffusion layer and thin barrier layer component embeds the extension layer expanded, so that medicine occurs to the quiet diffusion of body fluid or other liquid with substantially low than the speed diffusing out not destroyed medicine speed.
In a preferred embodiment of the present invention, the pharmaceutical composition produced controls having and maintains the mechanism of medicine from the speed of the drug diffusion of the part containing compositions to a great extent, and once compositions is destroyed, or when being exposed to liquid whole or in part, postpone the drug diffusion of medicine from the part containing compositions, and retain these two kinds of mechanism of mechanism of the basic ratio of medicine.Benefit of the present invention is, is intended to anyone destructive activity that will be difficult to by some types of Drug abuse, so from medicine rapid extraction medicine, and snuffing, swallow or inject.As a result, contrast with conventional formulation, use intensity and quality that the present invention produces the excitement of reduction inadequately, and reduce the excited ratio occurred.Therefore, wish by using this compositions can not realize required " excited " or excitement to reach " excited " or to stand excited misuser inadequately.In addition, less tonic effect, if had, realizes with low-down ratio.Except non-usage complexity with extracting method consuming time, otherwise by application the present invention, the main component of medicine will be sealed, and can not be separated from the medicine of the destruction produced, therefore reduce when snuffing, swallow or inject time total bioavailability.
In preferred embodiments, when this compositions is destroyed, contrast with complete unbroken compositions, discharge the percentage ratio substantially equaled lower than medicine.In preferred embodiments, within a period of time of the group be selected from 2 hours, 4 hours, 8 hours and form for 16 hours, contrast with complete unbroken tablet, within the mutually commensurability time, the compositions release destroyed is no more than 90%, more preferably no more than 75%, and more preferably no more than 60% medicine.
By in conventional manner body and analyzed in vitro technology, in such as body, blood plasma is measured or external drug dissolution, can measure mechanism described above and benefit.Use these technology, the medicine release in time existed in pharmaceutical composition can be monitored, and be expressed as the release percentage ratio of the medicine being present in this compositions at first.In a preferred embodiment of the present invention, when use pharmaceutical composition of the present invention is by physical damage, when then testing in Dissolution Rate Testing in vitro, the percentage ratio of the medicine of release will be quite low.
In the release characteristic of the product of the present invention discussed, the dosage form including the medicine of effective amount has by the USP slurry processes of American Pharmacopeia, use USP equipment I, with 100rpm (basket method) in the 900mL water buffer of pH1.6 and 7.2, the dissolution rate in vitro measured at 37 DEG C.
Preferably, release in vitro is the medicine discharging about 5% to about 50% (by weight) after 1h, discharge the medicine of about 20% to about 65% (by weight) after 4 hours, discharge the medicine of about 35% to about 85% (by weight) after 8 hours, and discharged the medicine of more than 60% (by weight) after 16 hours; More preferably after 1 hour after about 5% to about 40%, 4 hour about 15% to about 60%; After 8 hours about 40% to about 80%; And after 16 hours about 50% to about 90%; More preferably after 1 hour after about 10% to about 35%, 4 hour about 15% to about 55%; After 8 hours about 35% to about 75%; And after 16 hours about 50% to about 80%; Most preferably after 1 hour after about 10% to about 30%, 4 hour about 25% to about 60%; After 8 hours about 40% to about 80%; And after 16 hours about 55% to about 75%.By being often used in the dynamic (dynamical) conventional pharmacokinetic technology of drug characterization in human patients or other mammals, also mechanism described above and benefit can be measured.
The maximally related pharmacokinetic parameter understanding characteristic sum benefit of the present invention is Cmax (maximal plasma concentration of medicine and/or active metabolite) and AUC (under blood plasma concentration curve area: the integration of the Plasma concentrations versus time of medicine and/or active metabolite).In a preferred embodiment of the present invention, when pharmaceutical composition is applied to curee with physically destroyed form, be selected from use after 2 hours, 4 hours, 8 hours, 12 hours, 24 hours with a period of time of the group of 48 hours compositions after Cmax and/or AUC that realize with when identical with Cmax and/or AUC realized during complete form drug administration compositions, or lower than it, preferably about 20-75% lower than it.
One embodiment of the invention relate to compounding pharmaceutical compositions, so that when pharmaceutical composition is applied to curee with physically destroyed form, be selected from use after 2 hours, 4 hours, 8 hours, 12 hours, 24 hours and 48 hours compositions group a period of time after Cmax and/or AUC that produce of the medicine of destruction that realizes, lower than Cmax and/or AUC not using the bioequivalence compositions of the physical damage of the equivalent of anti-abuse methods to produce, preferably low about 20-75%." bioequivalence " pharmaceutical composition refers to containing identical medicine, and has the close set compound of AUC and Cmax of scope in 80% to 125% of AUC and Cmax with reference to pharmaceutical composition.
Another embodiment of the present invention relates to compounding pharmaceutical compositions, so that when pharmaceutical composition is applied to curee with physically destroyed form, be selected from use after 2 hours, 4 hours, 8 hours, 12 hours, 24 hours and 48 hours compositions group a period of time after the Cmax/AUC ratio that produces of the medicine of destruction that realizes, by the Cmax/AUC ratio that the bioequivalence medicine being the physical damage not containing anti-abuse methods produces, or lower than it, preferably low 20-75%.
Another preferred embodiment of the present invention is combination of oral medication, it comprises the medicine of pharmaceutical effective amount, wherein compounding pharmaceutical compositions, so that when pharmaceutical composition is used with complete form, at least 50%, preferably the medicine of amount of at least 60% discharges after 8 hours, and when pharmaceutical composition is used with physically destroyed form, be no more than 40%, preferably more than 35%, more preferably no more than 30%, and the medicine being most preferably not exceeding the amount of 25% discharges after 1h.Preferably, when pharmaceutical composition is used with physically destroyed form, be no more than 35%, more preferably no more than 30%, and the medicine being most preferably not exceeding the amount of 25% discharged in 15 minutes.
Another preferred embodiment of the present invention is combination of oral medication, it comprises the medicine of pharmaceutical effective amount, wherein compounding pharmaceutical compositions, so that when pharmaceutical composition is used with complete form, the medicine of the amount of at least 90% discharges after 1h, and when pharmaceutical composition is used with physically destroyed form, be no more than 75%, the medicine preferably more than the amount of 60% discharges after 1h.
The invention still further relates to combination of oral medication, it comprises the medicine of pharmaceutical effective amount, wherein compounding pharmaceutical compositions, so that when pharmaceutical composition is applied to curee with physically destroyed form, excited intensity be substantially equal to or less than use do not comprise the bioequivalence compositions be physically destroyed of anti-abuse methods after the intensity of excitement that realizes.Excitement is a kind of excited or extremely surging sensation, and it is used after the pharmaceutical composition containing medicine for central nervous system through going through through the misuser that is everlasting.Excited amount or intensity can be measured in a number of different manners.Measure excited method or technology sometimes with other illness of measurement, the method for such as pain or technology type are seemingly.Such as, excited amount or intensity can numeral or lineal scale be measured, and can to standing the amount of excitement of excited people or quantification of intensities or deciding grade and level.Such as, in some embodiments, can 0 to 10 scale measure excited amount or intensity, wherein excited a large amount is appointed as numeral 10, and is not excitedly appointed as numeral 0.Similarly, in some embodiments, measure excited amount or intensity with lineal scale, one end representative of its cathetus is not excited, and the other end of straight line represents the excitement of a large amount.In some embodiments, compounding pharmaceutical compositions, so that when pharmaceutical composition is applied to curee with physically destroyed form, excited intensity is substantially identical with the intensity used not containing the excitement realized after the physically destroyed bioequivalence compositions of anti-abuse methods, or effective selection of land lower than it is less than 10%, be more preferably less than 30%, and be more preferably less than 50%.
The release characteristic of pharmaceutical composition of the present invention preferably depends on pH.In addition, when the USP basket method by American Pharmacopeia, use USP equipment I, with 100rpm (basket method) in the water buffer of 900mLpH1.6 and 7.2, and when measuring at 37 DEG C, preferably at 40 DEG C, after storing 3 months under the relative humidity of 75%, the rate of release of preparation is without significant change (preferably, being less than the change of 10%).
All references cited herein by reference its entirety is incorporated at this.
Use following embodiment to confirm and the present invention is described.
Embodiment 1
Mannitol-90mg
Microcrystalline Cellulose-50mg
71G-128mg
Hydroxypropyl emthylcellulose, 2910 type-128mg
(METHOCEL
TMK4MCR)
Magnesium stearate-4mg
Method: mannitol, microcrystalline Cellulose,
71G and METHOCEL
tMk4MCR is sieved through #20 order, and mixes 10 minutes in a mixer.Magnesium stearate is sieved through #40 order, and joins blender, and mixes 5 minutes with lubrication mixture.Final mixture is pressed into 400-mg tablet weight, and the hardness between 8-15kp.
Embodiment 2
Mannitol-22.5mg
Microcrystalline Cellulose-12.5mg
71G-32mg
Hydroxypropyl emthylcellulose, 2910 type-32mg
(METHOCEL
TMK4MCR)
Magnesium stearate-1mg
Method: mannitol, microcrystalline Cellulose,
71G and METHOCEL
tMk4MCR is sieved through #20 order, and mixes 10 minutes in a mixer.Magnesium stearate is sieved through #40 order, and joins blender, and mixes 5 minutes with lubrication mixture.Final mixture is pressed into 100-mg tablet weight, and the hardness between 4-9kp.
Embodiment 3
Mannitol-135mg
Microcrystalline Cellulose-75mg
71G-192mg
Hydroxypropyl emthylcellulose, 2910 type-192mg (METHOCEL
tMk4MCR)
Magnesium stearate-6mg
Method: mannitol, microcrystalline Cellulose,
71G and METHOCEL
tMk4MCR is sieved through #20 order, and mixes 10 minutes in a mixer.Magnesium stearate is sieved through #40 order, and joins blender, and mixes 5 minutes with lubrication mixture.Final mixture is pressed into 600-mg tablet weight, and the hardness between 8-15kp.
Embodiment 4
Mannitol-70mg
Microcrystalline Cellulose-50mg
CARBOPOL
TM71G-128mg
Hydroxypropyl emthylcellulose, 2910 type-128mg (METHOCEL
tMk4MCR)
Cross-linking sodium carboxymethyl cellulose-20mg (
)
Magnesium stearate-4mg
Method: mannitol,
71G, microcrystalline Cellulose, METHOCEL
tMk4CR and
be sieved through #20 order, and mix 10 minutes in a mixer.Magnesium stearate is sieved through #40 order, and joins blender, and mixes 5 minutes with lubrication mixture.Final mixture is pressed into 400-mg tablet weight, and the hardness between 8-15kp.
and METHOCEL
tMthe compositions of (embodiment 4) is preferred preparation, because it provides the probability that relatively expands fast.Add super-disintegrant, such as
secondary expansion probability.Different extension layer tablet weight in addition shown in embodiment 1 to 3 create extension layer identical needed for feature.
Embodiment 5
Mannitol-45mg
Microcrystalline Cellulose-25mg
CARBOPOL
TM71G-64mg
Hydroxypropyl emthylcellulose, 2910 type-64mg (METHOCEL
tMk4MCR)
Magnesium stearate-2mg
Method: mannitol,
71G, microcrystalline Cellulose and METHOCEL
tMk4CR is sieved through #20 order, and mixes 10 minutes in a mixer.Magnesium stearate is sieved through #40 order, and joins blender, and mixes 5 minutes with lubrication mixture.Final mixture is pressed into 400-mg tablet weight, and the hardness between 8-15kp.
Embodiment 6
Extension layer tablet (embodiment 4)-370g
30D dispersion-300g
Calcium stearate powder-15g
Simethicone solid-0.15g
Pure water-85g
Method: the extension layer tablet will with 400mg Unit Weight loads conventional coating pan, and use conventional coating technology to incite somebody to action
nE30D, dimeticone emulsion 30%, calcium stearate and pure water suspension spray, on extension layer tablet, produce barrier layer.By first dimeticone emulsion being joined pure water, and be mixed with suspension.Mix after about 10 minutes, add calcium stearate powder and mix.Mix after about 15 minutes, use suitable homogenizer with middling speed by calcium stearate suspension homogenize 10 minutes.In the different container, add aequum
nE30D also mixes simultaneously, adds calcium stearate suspension.By final film coating suspension mixing about 20 minutes, be then sprayed on tablet.Then, the barrier layer tablet of coating processes 1-3 hour with stabilizing films at 60 DEG C.Then, the tablet of process is used for diffusion layer.In whole coating process, maintain the product temperature of 30-35 DEG C.The scope of spray rate is between 2-10g/min.
Embodiment 7
Extension layer tablet (embodiment 4)-370g
nE30D dispersion-300g
Calcium stearate-15g
Dimeticone emulsion solid-0.15g
Pure water-85g
Method: the preparation of film coating suspension is identical with previous embodiment with the coating processing on barrier layer.In this embodiment, after barrier coating terminates, apply diffusion layer coating immediately, then at 60 DEG C, process tablet 1-3 hour.In whole coating process, maintain the product temperature of 30-35 DEG C.The scope of spray rate is between 2-10g/min.
Embodiment 8
Extension layer tablet (embodiment 5)-400g
nE30D dispersion-150g
Calcium stearate-5g
Dimeticone emulsion solid-0.05g
Pure water-28g
Method: the extension layer tablet with 200mg Unit Weight is loaded conventional coating pan.Prepare similar to Example 6ly and contain
the film coating suspension of NE30D, calcium stearate, dimeticone emulsion 30% suspension and pure water, and use conventional coating technology to sparge on extension layer tablet, produce barrier layer.The applicating adn implementing example 7 of barrier layer, diffusion layer and processing procedure is similar.In whole coating process, maintain the product temperature of 30-35 DEG C.The scope of spray rate is between 2-10g/min.
Embodiment 9
Extension layer tablet (embodiment 3)-600g
nE30D dispersion-150g
Aerosil200-5g
Method: the extension layer tablet will with 600mg Unit Weight loads conventional coating pan, and use conventional coating technology to incite somebody to action
nE30D, Aerosil200 and pure water suspension spray, on extension layer tablet, produce barrier layer.By Aerosil200 being joined aequum
nE30D, and be mixed with film coating suspension.By final film coating suspension mixing about 20 minutes, be then sprayed on tablet.The applicating adn implementing example 7 and 8 of barrier layer, diffusion layer and processing procedure is similar.In whole coating process, maintain the product temperature of 30-35 DEG C.The scope of spray rate is between 2-10g/min.
Embodiment 10
Extension layer tablet (embodiment 2)-400g
nE30D dispersion-150g
Talcum-15g
Pure water-50g
Method: the extension layer tablet will with 100mg Unit Weight loads conventional coating pan, and use conventional coating technology to incite somebody to action
nE30D, Talcum and pure water dispersion are sprayed on extension layer tablet, produce barrier layer.By Talcum is mixed with the pure water of aequum, and mix, prepare barrier coating suspension.Mix after about 15 minutes, suspension was with middling speed homogenize 10 minutes.In different containers, add EUDRAGITNE30D.During mixing, add talc suspension, and the film coating suspension produced is mixed about 20 minutes, to be sprayed on tablet.The applicating adn implementing example 7 of barrier layer, diffusion layer and processing procedure, 8 similar with 9.Barrier layer is separated diffusion layer and extension layer, and also makes the resistance to crushing of tablet, resistance toly to smash to pieces and other physical methods of resistance to applying pressure.
Embodiment 11
Extension layer tablet (embodiment 4)-370g
nE30D dispersion-200g
rS30D dispersion-100g
Talcum-25g
Pure water-142g
Method: the extension layer tablet will with 400mg Unit Weight loads conventional coating pan, and use conventional coating technology to incite somebody to action
nE30D,
rS30D, Talcum and pure water suspension spray, in extension layer tablet, produce barrier layer.Film coating suspension preparation is closely similar with previous embodiment.Can pass through will
rS30D polymer mixes barrier coating to be increased
the impermeable feature of water of NE30D polymer.
Stop that the intensity of coated tablet and water impermeability characteristic dependence are in anticaking agents, such as Talcum, Aerosil200, calcium stearate, magnesium stearate and glyceryl monostearate.The stop coating of the dry of 5 – 95 % by weight that the starting weight based on extension layer tablet calculates provides relative compressive with water impervious tablet.Stop that the preferable range of coating is between 10-60 % by weight.If apply diffusion layer immediately after stop coating, then process together, then when broken, pulverize or crush time, stop coating and propagate polymerization thing coating are subsequently inseparable.
Embodiment 12
Stop coated tablet (embodiment 7)-475g
Oxycodone hydrochloride-37g
nE30D dispersion-175g
80-1.5g
200-2.0g
Pure water-100g
Method: complete after stopping coating, diffusion layer is applied in conventional coating pan immediately.By oxycodone hydrochloride,
80,
200 Hes
the drug polymer coatings of NE30D suspension composition sparges and stops on coated tablet.By first will
80 pure water joining aequum, and mixing carrys out supending.Mixing continues about more than 10 minute.During mixing, will
200 powder join the suspension of previous steps, and mix about 1 minute.In different containers, add the EUDRAGITNE30D of aequum, and mix simultaneously, add oxycodone hydrochloride powder, and mixing continue about more than 15 minute to obtain uniform suspension.During mixing, add the suspension containing Tween-Aerosil, and by final suspension mixing about 20 minutes, be then sprayed on tablet.Then, the tablet of diffusion layer coating is processed 1-3 hour at 60 DEG C, with stable thin layer.In whole coating process, maintain the product temperature of 30-35 DEG C.The scope of spray rate is between 5-15g/min.
Embodiment 13
Stop coated tablet (embodiment 7)-475g
Oxycodone hydrochloride-37g
nE30D dispersion-275g
Calcium stearate-6g
Dimeticone emulsion solid-0.06g
Pure water-34.4g
Method: complete after stopping coating, diffusion layer coating is applied in conventional coating pan immediately.By first dimeticone emulsion being joined pure water, and mixing carrys out supending.Mix after about 10 minutes, add calcium stearate powder and mix.Mix after about 15 minutes, use suitable homogenizer with middling speed by calcium stearate suspension homogenize 10 minutes.In different containers, add the EUDRAGITNE30D of aequum, and mix simultaneously, add oxycodone hydrochloride powder, and continue to mix about 15 minutes to obtain uniform suspension.In this uniform suspension, add calcium stearate suspension.By final film coating suspension mixing about 20 minutes, be then sprayed on tablet.Then, dispersion layer tablet is processed 1-3 hour with stabilizing films at 60 DEG C.In whole coating process, maintain the product temperature of 30-35 DEG C.The scope of spray rate is between 5-15g/min.
Embodiment 14
Stop coated tablet (embodiment 11)-485g
Oxycodone hydrochloride-74g
nE30D dispersion-350g
Tween80-2g
Calcium stearate-11g
Dimeticone emulsion solid-0.11g
Pure water-60g
Method: complete after stopping coating, diffusion layer coating is applied in conventional coating pan immediately.Will by oxycodone hydrochloride,
the diffusion layer of NE30D, calcium stearate, dimeticone emulsion dispersion 30% and pure water suspension composition is sprayed to and stops on coated tablet.By first dimeticone emulsion being joined pure water, and mixing carrys out supending.Mix after about 10 minutes, add calcium stearate powder and mix.Mix after about 15 minutes, use suitable homogenizer with middling speed by calcium stearate suspension homogenize 10 minutes.In different containers, add the EUDRAGITNE30D of aequum, and mix simultaneously, add
80, and continue mixing about 10 minutes.After this, add oxycodone hydrochloride powder, and mix.Mix after about 15 minutes, add calcium stearate suspension.By final film coating suspension mixing about 20 minutes, be then sprayed on tablet.Then, dispersion layer tablet is processed 1-3 hour with stabilizing films at 60 DEG C.In whole coating process, maintain the product temperature of 30-35 DEG C.The scope of spray rate is between 5-15g/min.
Embodiment 15
Stop coated tablet (embodiment 8)-450g
Oxycodone hydrochloride-10g
nE30D dispersion-100g
Aerosil200-2g
Pure water-100g
Method: complete after stopping coating, diffusion layer coating is applied in conventional coating pan immediately.Will by oxycodone hydrochloride,
nE30D,
200 and the diffusion layer of pure water dispersion composition be sprayed to and stop on coated tablet, then the tablet of diffusion layer coating is processed 1-3 hour with stabilizing films at 60 DEG C.For the preparation of film coating suspension, reference example 12.
Embodiment 16
Stop coated tablet (embodiment 7)-475g
Synkonin-9.25g
nE30D dispersion-155g
200 powder-5g
-1.5g
Pure water-185g
Method: complete after stopping coating, diffusion layer coating is applied in conventional coating pan immediately.By first will
80 Hes
200 powder join pure water, and suspension mixing is prepared diffusion layer dispersion in about 10 minutes.Then, Synkonin powder is joined in suspension.By suspension mixing about 15 minutes, to realize being uniformly distributed of medicine.In different containers, add the EUDRAGITNE30D of aequum.During mixing, activity-Tween-Aerosil suspension is joined EUDRAGITNE30D dispersion, and mixing is not less than 20 minutes, is then sprayed to and stops on coated tablet.Then, the tablet of diffusion layer coating is processed 1-3 hour with stabilizing films at 60 DEG C.In whole coating process, maintain the product temperature of 30-35 DEG C.The scope of spray rate is between 5-15g/min.
Embodiment 17
Stop coated tablet (embodiment 7)-475g
Morphine sulfate-55.6g
nE30D dispersion-275g
Aerosil200-5.0g
Pure water-150g
Method: complete after stopping coating, diffusion layer coating is applied in conventional coating pan immediately.Will by morphine sulfate,
the diffusion layer of NE30D, Aerosil200 and pure water dispersion composition is sprayed to and stops on coated tablet, then the tablet of diffusion layer coating is processed 1-3 hour with stabilizing films at 60 DEG C.By first will
200 powder join pure water, and suspension mixing is prepared diffusion layer dispersion in about 10 minutes.Then, morphine sulphate powder is joined suspension.Mixing, until obtain unit for uniform suspension.Suspension was with middling speed homogenize about 10 minutes.In different containers, add the EUDRAGITNE30D of aequum.During mixing, medicine-Aerosil suspension is joined EUDRAGITNE30D dispersion, and mixing is not less than 20 minutes, is then sprayed to and stops on coated tablet.
Embodiment 18
Stop coated tablet (embodiment 7)-475g
Dihydromorphinone hydrochloride-14.8g
nE30D dispersion-250g
200-5.0g
Pure water-100g
Method: complete after stopping coating, diffusion layer coating is applied in conventional coating pan immediately.Will by dihydromorphinone hydrochloride,
nE30D,
200 and the diffusion layer of pure water dispersion composition be sprayed to and stop on coated tablet, then the tablet of diffusion layer coating is processed 1-3 hour with stabilizing films at 60 DEG C.In whole coating process, maintain the product temperature of 30-35 DEG C.The scope of spray rate is between 5-15g/min.For the preparation of suspension, with reference to previous embodiment.
Embodiment 19
Stop coated tablet (embodiment 7)-475g
Oxymorphone hydrochloride-37g
nE30D dispersion-220g
80-2.5g
200-5.0g
Pure water-100g
Method: complete after stopping coating, diffusion layer is applied in conventional coating pan immediately.Will by oxymorphone hydrochloride,
nE30D,
80,
be sprayed to the diffusion layer of pure water dispersion composition and stop on coated tablet.By first will
80 Hes
200 powder join pure water, and suspension mixing is prepared diffusion layer dispersion in about 10 minutes.Then, oxymorphone hydrochloride powder is joined suspension.Suspension is mixed about 15 minutes to obtain being uniformly distributed of medicine.In different containers, add the EUDRAGITNE30D of aequum.During mixing, activity-Tween-Aerosil suspension is joined EUDRAGITNE30D dispersion, and mixing is not less than 20 minutes, is then sprayed to and stops on coated tablet.Then, the tablet of diffusion layer coating is processed 1-3 hour with stabilizing films at 60 DEG C.In whole coating process, maintain the product temperature of 30-35 DEG C.The scope of spray rate is between 5-15g/min.
Embodiment 20
Stop coated tablet (embodiment 8)-475g
Hydrochloric acid dexmethylphenidate-10g
nE30D dispersion-100g
Aerosil200-1g
Pure water-100g
Method: complete after stopping coating, diffusion layer is applied in conventional coating pan immediately.Will by hydrochloric acid dexmethylphenidate,
nE30D,
200 and the diffusion layer of pure water dispersion composition be sprayed to and stop on coated tablet, then the tablet of diffusion layer coating is processed 1-3 hour with stabilizing films at 60 DEG C.In whole coating process, maintain the product temperature of 30-35 DEG C.The scope of spray rate is between 5-15g/min.
Embodiment 21
Stop coated tablet (embodiment 10)-450g
Zaleplon-20g
nE30D dispersion-100g
200-1g
80-5g
Pure water-100g
Method: complete after stopping coating, diffusion layer is applied in conventional coating pan immediately.Will by Zaleplon,
nE30D,
200,
80 and the diffusion layer of pure water dispersion composition be sprayed to and stop on coated tablet.By first will
80 Hes
200 powder join pure water, and suspension mixing is prepared diffusion layer dispersion in about 10 minutes.Then, Zaleplon powder is joined in suspension.By suspension mixing about 15 minutes and homogenize 10 minutes, to realize being uniformly distributed of medicine.In different containers, add the EUDRAGITNE30D of aequum.During mixing, activity-Tween-Aerosil suspension is joined EUDRAGITNE30D dispersion, and mixing is not less than 20 minutes, is then sprayed to and stops on coated tablet.Then, the tablet of diffusion layer coating is processed 1-3 hour with stabilizing films at 60 DEG C.In whole coating process, maintain the product temperature of 30-35 DEG C.The scope of spray rate is between 5-15g/min.
Embodiment 22
Stop coated tablet (embodiment 9)-695g
Propranolol hydrochloride-80g
nE30D dispersion-150g
200-5g
solution-1g
Pure water-100g
Method: complete after stopping coating, diffusion layer is applied in conventional coating pan immediately.Will by propranolol hydrochloride,
200,
80,
the diffusion layer of NE30D and pure water dispersion composition is sprayed to and stops on coated tablet, then the tablet of diffusion layer coating is processed 1-3 hour with stabilizing films at 60 DEG C.In whole coating process, maintain the product temperature of 30-35 DEG C.The scope of spray rate is between 5-15g/min.
Embodiment 23
Stop coated tablet (embodiment 6)-475g
Tramadol hydrochloride-92.6g
nE30D dispersion-290g
80-0.5g
200-5g
Pure water-250g
Method: complete after stopping coating, diffusion layer is applied in conventional coating pan immediately.Will by tramadol hydrochloride,
nE30D,
80,
200 and the diffusion layer of pure water dispersion composition be sprayed to and stop on coated tablet, then the tablet of diffusion layer coating is processed 1-3 hour with stabilizing films at 60 DEG C.In whole coating process, maintain the product temperature of 30-35 DEG C.The scope of spray rate is between 5-15g/min.
Embodiment 24 (drug product, conventional immediate release)
Stop coated tablet (embodiment 8)-450g
Oxycodone diffusion coating:
Oxycodone hydrochloride-10g
nE30D dispersion-100g
200-1g
Pure water-100g
Sub-coating, acetylamino benzophenone (Acetaminophenone) coating and sealing coating
Sub-coating-the 100g of 5%HPMC solution
Acetylamino benzophenone powder-2000g
10%HPMC solution-1000g
Pure water-1000g
5%HPMC seals coating-100g
Method: complete after stopping coating, oxycodone hydrochloride diffusion layer is applied in conventional coating pan immediately.Will by oxycodone hydrochloride,
nE30D,
200 and the diffusion layer of pure water suspension composition be sprayed to and stop on coated tablet.Then the tablet of diffusion layer coating is processed 1-3 hour with stabilizing films at 60 DEG C.Once processing procedure completes, the sub-coating of application 5%HPMC, applies acetylamino benzophenone coating subsequently.Acetylamino benzophenone HPMC suspension is sprayed on tablet with 5-25g/min.By first 10%METHOCEL solution being mixed with the pure water of aequum, then active medicine being suspended, mixing simultaneously, prepare acetylamino benzophenone suspension.By suspension mixing about 15 minutes, then homogenize 10 minutes, was then sprayed on tablet.Alternatively, use powder feeder to be spread in coating pan by active agent powder, and use nozzle spray 10%HPMC solution.Keep the product temperature of about 30-35 DEG C.Once after applying all suspensions, application HPMC seals coating.Under product temperature between 38-40 DEG C, by tablet drying 5 minutes, then take out from coating pan.
Embodiment 25
Stop coated tablet-475g
diffusion layer coating:
Oxycodone hydrochloride-37g
nE30D dispersion-275g
80-2.5g
Calcium stearate-6g
Simethicone solid-0.06g
Pure water-34.4g
sustained release layer coating:
nE30D dispersion-30g
HPMC10% solution-30g
200-2.5g
Pure water-66g
Complete after stopping coating, diffusion layer is applied in conventional coating pan immediately.Will by oxycodone hydrochloride,
nE30D,
80, the diffusion layer of calcium stearate, dimeticone emulsion 30% dispersion and pure water suspension composition is sprayed to and stops on coated tablet, subsequent spray sustained release film coating suspension.By inciting somebody to action
nE30D, 10%HPMC solution,
200 and pure water mixing (about 15 minutes) prepare sustained release film coating suspension.After completing coating, then the tablet of coating processes 1-3 hour with stabilizing films at 60 DEG C.In whole coating process, maintain the product temperature of 30-35 DEG C.The scope of spray rate is between 5-15g/min.
Embodiment 26
Diffusion layer tablet (embodiment 13)-600g
Opadry (Opadry) 85F18422 white powder-50g
Pure water-250g
After completing diffusion coating, color coating is applied to conventional coating pan immediately.By Opadry powder suspension is prepared color film coating suspension in pure water.About 300g color suspension is sprayed to diffusion layer coated tablet with the spray rate of 5-15g/min.In whole process, maintain the product temperature of 36-38 DEG C.
Embodiment 27
Stop coated tablet (embodiment 8)-450g
Oxycodone hydrochloride-10g
Morphine sulfate-20g
30D dispersion-125g
80-1.0g
200-2.0g
Pure water-100g
Method: complete after stopping coating, diffusion layer is applied in conventional coating pan immediately.Will by oxycodone hydrochloride, morphine sulfate,
80,
200 Hes
the drug polymer coatings of NE30D suspension composition is sprayed to and stops on coated tablet.In whole coating process, maintain the product temperature of 30-35 DEG C.The scope of spray rate is between 5-15g/min.
Embodiment 28
Stop coated tablet (embodiment 7)-475g
Oxycodone hydrochloride-9.3g
Morphine sulfate-18.5g
30D dispersion-275g
80-2.0g
200-2.5g
Pure water-100g
Method: complete after stopping coating, diffusion layer coating is applied in conventional coating pan immediately.Will by oxycodone hydrochloride, morphine sulfate,
80,
200 Hes
the drug polymer coatings of NE30D suspension composition is sprayed to and stops on coated tablet.In whole coating process, maintain the product temperature of 30-35 DEG C.The scope of spray rate is between 5-15g/min.
The anti-abuse capsule preparations of embodiment 29-
extension layer
barrier layer
diffusion layer
sustained release coating
color coating
Opadry 85Fl8422 powder-30mg
Pure water--------
Method: mannitol, microcrystalline Cellulose,
71G and METHOCEL
tMk4MCR is selected by #20 mesh sieve, and mixes 10 minutes in a mixer.Magnesium stearate is selected by #40 mesh sieve, and joins in blender, and mixes 5 minutes with lubrication mixture.Final mixture is encapsulated in HPMC size #2 capsule with 300-mg weight package.Extension layer capsule loads conventional coating pan, and will
nE30D, calcium stearate, dimeticone emulsion and pure water suspension spray, on capsule, produce barrier layer.Complete after stopping coating, diffusion layer is applied to conventional coating pan immediately, apply sustained release coating subsequently.Then, sustained release coated capsule processes 1-3 hour with stabilizing films at 60 DEG C.After processing procedure, application color coating.In whole coating process, maintain the product temperature of 30-35 DEG C.The scope of spray rate is between 5-15g/min.
The anti-abuse Bolus formulation of embodiment 30-
extension layer
barrier layer
diffusion layer
tablet formulation
AvicelPH102-100mg
AvicelPH200-100mg
Magnesium stearate-8mg
color coating
Opadry 85F18422 powder-30mg
Pure water--------
One or more active component can be placed in one or more single pill.In some embodiments, two or more dissimilar pills can use together, and wherein the pill of every type contains different active component.
Method: mannitol, microcrystalline Cellulose,
71G and METHOCEL
tMk4MCR is selected by #20 mesh sieve, and is loaded into fluidized bed dryer/coating device that top-spray coating nozzle is housed.10%METHOCEL solution as binder solution spraying with by powder granulation.After completing required granulation, the humidity level of particle drying to about 2%.Dry granule takes out from fluid bed machine, and uses suitable milling machine, and such as specific dimensions made by Stokes oscillating granulator.Then, the dried particles with certain size is loaded into identical fluidized bed dryer/coating device, and will
nE30D,
rS30D, Talcum and pure water dispersion are sprayed to pill/granule, produce barrier layer.Complete after stopping coating, apply diffusion layer immediately.By oxycodone hydrochloride,
nE30D,
200 and the diffusion layer of pure water suspension composition be sprayed to and stop on coated capsule, then the pill of diffusion layer coating is processed at 60 DEG C 1-3 hour with stabilizing films.In whole coating process, maintain the product temperature of 30-35 DEG C.The scope of spray rate is between 5-15g/min.Then, use suitable blender that the pill of process is mixed about 10 minutes with AvicelPH102 and AvicelPH200.Magnesium stearate is joined blender, and mixes 5 minutes.Final mixture is pressed into the hardness of 766mg tablet weight and 8-16kp.Then, the tablet of compacting is loaded into conventional coating pan, for color coating.
Embodiment 31
extension layer
barrier layer
diffusion layer
color coating
Opadry 85F18422 powder-30mg
Pure water---------
When suitably (complete) take to take with the ground form of same piece agent formulation compared with time, the rate of release of the tablet prepared according to embodiment 31 by contrast, tests this preparation about oxycodone.Result is reported in Fig. 1, and display is when tablet is suitably taken, and most drug is discharged in patient.
The tablet comprising the pharmaceutical composition of embodiment 31 uses sharp equipment, and such as cutter and shears are cut into 2 and 8.Extension layer powder is completely removed.Fig. 4 shows the contrast of this speed.This confirms when tablet of the present invention is by physical damage, and the secondary or physical bond between diffusion layer and barrier layer is retained substantially.The relative surface area of diffusion layer only increases on edge, prevents the remarkable increase of drug release.Therefore, in some embodiments, even when the dosage form containing pharmaceutical composition of the present invention is by physical damage, contrast with complete dosage form, medicine keeps identical release characteristic substantially.